Clarithromycin 500 Mg Film-Coated Tablets

Document: spc-doc_PL 42357-0041 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Clarithromycin 500 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 500 mg clarithromycin.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Light yellow coloured, oval shaped, biconvex film-coated tablets, with ‘D’ debossed on one side and ‘63’ on the other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Clarithromycin is indicated in adults and children 12 years and older.

Clarithromycin is indicated for the treatment of the following infections caused by clarithromycin susceptible organisms (see sections 4.4 and 5.1).

• Bacterial pharyngitis

• Mild to moderate community-acquired pneumonia

• Acute bacterial sinusitis (adequately diagnosed)

• Acute exacerbation of chronic bronchitis

• Skin and soft tissue infections of mild to moderate severity.

• In appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer healing medicinal product for the eradication of Helicobacter pylori in adult patients with Helicobacter pylori-associated ulcers (see section

4.2).

4.2 Posology and method of administration

Posology:

The dosage of Clarithromycin film-coated tablets depends on the type and severity of the infection and has to be defined in any case by the physician.

Adults and adolescents:

• Standard dosage: The usual dose is 250mg twice daily (in the morning and in the evening)

• High dosage treatment (severe infections): The usual dose may be increased to 500 mg twice daily in severe infections.

Eradication of Helicobacter pylori in adults:

In patients with gastro-duodenal ulcers due to Helicobacter pylori infection clarithromycin is given in a dosage of 500 mg twice daily. The national recommendations for Helicobacter pylori eradication have to be considered.

Children younger than 12 years of age:

Clinical trials have been conducted using clarithromycin pediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin pediatric suspension (granules for oral suspension). There are insufficient data to recommend a dosage regimen for use of the clarithromycin IV formulation in patients less than 18 years of age.

Children older than 12 years: As for adults.

The usual duration of treatment is 6 to 14 days.

Duration of therapy:

The duration of therapy with clarithromycin depends on the type and severity of the infection.

The usual duration of treatment is 6 to 14 days.

Dosage in renal functional impairment:

In patients with renal impairment with creatinine clearance less than 30 mL/min, the dosage of clarithromycin should be reduced by one-half, i.e. 250 mg once daily, or 250 mg twice daily in more severe infections. Treatment should not be continued beyond 14 days in these patients.

Patients with hepatic impairment:

Caution should be exercised when administrating clarithromycin in patients with hepatic impairment (see section 4.3. and 4.4).

Method of administration:

The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water).

Clarithromycin may be given irrespective of food intake.

4.3 Contraindications

Clarithromycin is contraindicated in patients with known hypersensitivity to the active substance clarithromycin, to other macrolides or to any of the excipients listed in section 6.1.

Concomitant administration of clarithromycin and any of the following drugs is[]contraindicated: astemizole, cisapride, pimozide, terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointe (see section 4.5).

Concomitant administration with ticagrelor or ranolazine is contraindicated.

Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity.

Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointe (see sections 4.4 and 4.5).

Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis. (see section 4.5).

Clarithromycin should not be given to patients with hypokalaemia (risk of prolongation of QT-time).

Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.

As with other strong CYP3A4 inhibitors, Clarithromycin should not be used in patients taking colchicine.

4.4 Special warnings and precautions for use

The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy (see section 4.6).

Clarithromycin should be reserved for documented Group A beta-hemolytic streptococcal pharyngitis when treatment with beta-lactams cannot be used.

Caution is advised in patients with severe renal insufficiency (see section 4.2). When renal function is poor, dosage of clarithromycin should be suitably reduced depending on the degree of the impairment (see section 4.2). In elderly patients, the possibility of renal impairment should be considered.

Clarithromycin is principally excreted by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment.

Cases of fatal hepatic failure (see section 4.8) have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Therefore, discontinuation of clarithromycin therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Drugs inhibiting peristalsis should be avoided.

As known for other macrolides, clarithromycin may cause exacerbation or aggravation of myasthenia gravis and should therefore be used with caution in patients with myasthenia gravis.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5). Concomitant administration of clarithromycin and colchicine is contraindicated (see section 4.3).

Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam (see section 4.5).

Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment.

Due to the risk for QT prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe cardiac insufficiency, hypomagnesemia, bradycardia (<50 bpm), or when co-administered with other medicinal products associated with QT prolongation (see section 4.5). Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see section

4.3).

Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with additional appropriate antibiotics.

Skin and soft tissue infections of mild to moderate severity: These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta-lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme, especially when patient is treated with a CYP3A4 substrate having narrow therapeutic index (like carbamazepin) and/or is metabolised to a large extent by this enzyme clarithromycin should not be used unless clearly indicated (see section 4.5).

HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered (see section 4.5).

Oral hypoglycemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents (such as sulphonylurias) and/or insulin can result in significant hypoglycemia. Careful monitoring of glucose is recommended (see section 4.5).

Oral anticoagulants: There is a risk of serious hemorrhage and significant elevations in International Normalized Ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.

Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug-resistant organisms.

Long-term use may, as with other antibiotics, result in colonization with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.

Patients who are hypersensitive to lincomycin or clindamycin may also be hypersensitive to clarithromycin. Therefore, caution is required when prescribing clarithromycin for such patients.

Attention should also be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.

4.5 Interaction with other medicinal products and other forms of interaction

The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects:

Cisapride, pimozide, astemizole and terfenadine Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see section 4.3).

Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see section 4.3). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in a two to three fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.

Ergotamine/dihydroergotamine

Postmarketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and these medicinal products is contraindicated (see section

4.3).

HMG-CoA Reductase Inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3) as these statins are extensively metabolized by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin.Use of a statin that is not dependent on CYP3A metabolism (e.g.fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.

Effects of other medicinal products on clarithromycin

Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inhibitor administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.

The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.

Etravirine

Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.

Concomitant administration of clarithromycin and antimycotics of the azole class (fluconazol, itraconazole, ketoconazole) increases the risk of cardiac toxicity (prolonged QT-interval, Torsades des Pointes, cardiac arrest).

Ritonavir

A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin C_max increased by 31%, C_min increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function.

However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_cr 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_cr<30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 gm/day should not be coadministered with ritonavir.

Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see section below, Bidirectional drug interactions)

Effect of clarithromycin on other medicinal products

CYP3A-based interactions

Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolized by this enzyme.

Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin, see section 4.4), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

Antiarrhythmics

There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during coadministration of clarithromycin with these drugs. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy.

There have been post marketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.

Oral hypoglycemic agents/Insulin

After concomitant administration of Clarithromycin with insulin and other anti-diabetic medicinal products, hypoglycaemia has been observed.

The mechanism for this phenomenon is not fully understood, though it may be related to pharmacokinetic interaction between clarithromycin and some oral antidiabetics. In healthy subjects, the use of clarithromycin 250 mg twice daily for two days increased glibenclamide plasma levels (0.875 mg single dose) with 1.3 fold, possibly by inhibiting P-glycoprotein in the intestinal wall.

With certain hypoglycemic drugs such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Careful monitoring of glucose is recommended.

Warfarin

The use of clarithromycin in patients receiving warfarin may result in potentiation of the effects of warfarin. Prothrombin time should be frequently monitored in these patients.

Omeprazole

Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (C_max, AUC_0-24, and t_1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.

There are no in-vivo human data available describing an interaction between clarithromycin and the following drugs: aprepitant, eletriptan, halofantrine, and ziprasidone. However, because in vitro data suggest these drugs are CYP3A substrates, caution should be used when they are co-administered with clarithromycin.

Eletriptan should not be co-administered with CYP3A inhibitors such as clarithromycin.

Cyclosporin, tacrolimus and sirolimus

Concomitant use of oral clarithromycin has resulted in more than a 2-fold increase of the Cmin levels of both cyclosporin and tacrolimus. Similar effects are also expected for sirolimus. When initiating treatment with clarithromycin in patients already receiving any of these immunosuppressive agents, cyclosporin, tacrolimus or sirolimus plasma levels must be closely monitored and their doses decreased as necessary. When clarithromycin is discontinued in these patients, close monitoring of plasma levels of cyclosporine, tacrolimus or sirolimus, is again necessary to guide dose adjustment.

Sildenafil, tadalafil, and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.

Theophylline, carbamazepine

Results of clinical studies indicate there was a modest but statistically significant (pD0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with clarithromycin. Dose reduction may need to be considered.

Tolterodine

The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metabolizer population.

Triazolobenzodiazepines (e.g. alprazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration.

Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.

There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

Other drug interactions

Aminoglycosides

Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides (see section 4.4).

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.4).

Digoxin

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

Zidovudine

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine to allow for a 4-hour interval between each medication. This interaction does not appear to occur in paediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered via intravenous infusion.

Phenytoin and Valproate

There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs not thought to be metabolized by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported

Bi-directional drug interactions

Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14(R)-hydroxyclarithromycin, with a 28% increase in the AUC of atazanavir.

Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function.

For patients with moderate renal function (creatinine clearance 30 to 60 ml/min), the dose of clarithromycin should be decreased by 50%.

For patients with creatinine clearance <30 ml/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation, such as immediate-release tablets, sachet, or paediatric suspensions (not all presentations may be marketed).

Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors.

Calcium Channel Blockers

Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly. Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction: Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin.

Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.

Saquinavir

Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bidirectional drug interaction.

Concomitant administration of clarithromycin (500 mg bid) and saquinavir (soft gelatine capsules, 1200 mg tid) to 12 healthy volunteers resulted in steady-state area under the curve (AUC) and maximum concentration (Cmax) values of saquinavir, which were 177% and 187% higher than those seen with saquinavir alone.

Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone.

No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied.

Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule.

Observations from drug interaction studies done with unboosted saquinavir may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is coadministered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see section above, effect of other medicinal products on clarithromycin).

4.6 Fertility, pregnancy and lactation

Pregnancy:

The safety of clarithromycin for use during pregnancy has not been established. Data on the use of clarithromycin during the first trimester of more than 200 pregnancies show no clear evidence of teratogenic effects or adverse effects on the health of the neonate. Data from a limited number of pregnant women exposed in the first trimester indicate a possible increased risk of abortions. To date no other relevant epidemiological data are available.

Data from animal studies have shown reproductive toxicity (see section 5.3). Based on variable results obtained from studies in mice, rats, rabbits and monkeys, the possibility of adverse effects on embryofoetal development cannot be excluded. The risk for humans is unknown. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk.

Breast-feeding:

The safety of clarithromycin for use during breast feeding of infants has not been established. Clarithromycin and its active metabolite are excreted in breast milk. Therefore, diarrhoea and fungus infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility of sensitisation should be borne in mind. The benefit of treatment of the mother should be weighed against the potential risk for the infant.

Fertility

There is no data available on the effect of clarithromycin on fertility in humans. In rats, the limited data available do not indicate any effects on fertility.

4.7 Effects on ability to drive and use machines

There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

4.8 Undesirable effects

a. Summary of the safety profile

The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics. (see section b of section 4.8)

There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.

b. Tabulated summary of adverse reactions

The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended-release tablets and modified-release tablets.

The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (>1/10), common (> 1/100 to < 1/10), uncommon (>1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed.

System Organ Class	Very common (>1/10)	Common (> 1/100 to < 1/10)	Uncommon (>1/1,000 to < 1/100)	Not Known (cannot be estimated from the available data)
Infections and infestations			Cellulitis¹, candidiasis, gastroenteritis²,infection³, vaginal infection	Pseudomembranous colitis, erysipelas
Blood and lymphatic system			Leukopenia, • 4 neutropenia , thrombocythemia³, eosinophilia⁴	Agranulocytosis, thrombocytopenia
Immune system			Anaphylactoid reaction¹,	Anaphylactic

disorders⁵		hypersensitivity	reaction, angioedema
Metabolism and nutrition disorders		Anorexia, decreased appetite
Psychiatric disorders	Insomnia	Anxiety, nervousness³, screaming³	Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams
Nervous system disorders	Dysgeusia, headache, taste perversion	Loss of consciousness¹, dyskinesia¹, dizziness, somnolence⁶, tremor	Convulsion, ageusia, parosmia, anosmia , paraesthesia
Ear and labyrinth disorders		Vertigo, hearing impaired, tinnitus	Deafness
Cardiac disorders		Cardiac arrest¹, atrial fibrillation¹, electrocardiogram QT prolonged⁷, extrasystoles¹, palpitations	Torsade de pointes⁷, ventricular tachycardia⁷
Vascular disorders	Vasodilation¹		Hemorrhage⁸
Respiratory, thoracic and mediastinal disorder		Asthma¹, epistaxis², pulmonary embolism¹
Gastrointestinal disorders	Diarrhea⁹, vomiting, dyspepsia, nausea, abdominal pain	Esophagitis¹, gastrooesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, abdominal distension⁴, constipation, dry mouth, eructation, flatulence,	Pancreatitis acute, tongue discolouration, tooth discoloration
Hepatobiliary disorders	Liver function test abnormal	Cholestasis⁴, hepatitis⁴, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased⁴	Hepatic failure¹⁰, jaundice hepatocellular
Skin and subcutaneous tissue disorders	Rash, hyperhidrosis	Dermatitis bullous¹, pruritus, urticaria, rash maculo-papular³	Stevens-Johnson syndrome⁵, toxic epidermal necrolysis⁵, drug rash with eosinophilia and systemic symptoms (DRESS), acne

Musculoskeletal and connective tissue disorders			Muscle spasms³, musculoskeletal stiffness¹, myalgia²	Rhabdomyolysis^2,11, myopathy
Renal and urinary disorders			Blood creatinine increased¹, blood urea increased¹	Renal failure, nephritis interstitial
General disorders and administration site conditions	Injection site phlebitis¹	Injection site pain¹, injection site inflammation¹	Malaise⁴, pyrexia³, asthenia, chest pain⁴, chills⁴, fatigue⁴
Investigations			Albumin globulin ratio abnormal¹, blood alkaline phosphatase increased⁴, blood lactate dehydrogenase increased⁴	International normalised ratio increased⁸, prothrombin time prolonged⁸, urine color abnormal

¹ ADRs reported only for the Powder for Solution for Injection formulation ²ADRs reported only for the Extended-Release Tablets formulation

³ ADRs reported only for the Granules for Oral Suspension formulation

⁴ ADRs reported only for the Immediate-Release Tablets formulation ^5,7,9,10See section a)

^6,8,11See section c)

c. Description of selected adverse reactions

Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.

In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).

There have been rare reports of clarithromycin ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibiotic.

Special population: Adverse Reactions in Immunocompromised Patients (see section e)

d. Paediatric populations

Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension. There are insufficient data to recommend a dosage regimen for use of the clarithromycin IV formulation in patients less than 18 years of age.

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

e. Other special populations

Immunocompromised patients

In AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of Human Immunodeficiency Virus (HIV) disease or intercurrent illness.

In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1000 mg and 2000mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1000mg and 2000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000mg of clarithromycin.

In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1000mg or 2000mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4000mg daily for all parameters except White Blood Cell.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of intoxification:

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastro-intestinal symptoms. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokaliaemia and hypoxaemia.

Therapy of intoxification:

There is no specific antidote on overdose. Serum levels of clarithromycin cannot be reduced by haemodialysis or peritoneal dialysis.

Adverse reactions accompanying over dosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

Severe acute allergic reactions may be seen very rarely, e.g. anaphylactic shock. At the first signs of hypersensitivity reactions therapy with clarithromycin must be discontinued and the required measures should be initiated immediately.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

General properties

ATC Classification:

Pharmacotherapeutic group: Macrolides ATC Code: J01FA09

Mode of action:

Clarithromycin, a semi-synthetic derivative of erythromycin, exerts its antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than the MICs of erythromycin.

The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this metabolite are equal or two-fold higher than the MICs of the parent compound, except for H. influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.

PK/PD Relationship

Clarithromycin is extensively distributed in body tissues and fluids. Because of high tissue penetration, intracellular concentrations are higher than serum concentrations.

The most important pharmacodynamic parameters for predicting macrolide activity are not conclusively established. The time above MIC (T/MIC) may correlate best with efficacy for clarithromycin, however since clarithromycin concentrations achieved in respiratory tissues and epithelial lining fluids exceed those in plasma, using parameters based on plasma concentrations may fail to predict accurately the response for respiratory tract infections.

Mechanism of Resistance:

Resistance mechanisms against macrolide antibiotics include alteration of the target site of the antibiotic or are based on the modification and/or active efflux of the antibiotic.

Resistance development can be mediated via chromosomes or plasmids, be induced to exist constitutively. Macrolide-resistant bacteria generate enzymes which lead to methylation of residual adenine at ribosomal RNA and consequently to inhibition of the antibiotic binding to the ribosome. Macrolide-resistant organisms are generally cross-resistant to lincosamides and streptogramine B based on methylation of the ribosomal binding site. Clarithromycin ranks among the strong inducers of this enzyme as well. Furthermore, macrolides have a bacteriostatic action by inhibiting the peptidyl transferase of ribosomes.

A complete cross-resistance exists among clarithromycin, erythromycin and azithromycin. Methicillin-resistant staphyllococci and penicillin-resistant Streptococcus pneumonia are resistant to macrolides such as clarithromycin.

Breakpoints:

The following breakpoints for clarithromycin, separating susceptible organisms from resistant organisms, have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST) 2010-04-27 (v 1.1)

Species-related breakpoints (S</R>)

Non

species

break-

points^A

S</R>

Enterobacteriaceae

Pseudomonas

Acinetobacter

Staphylococcus

Enterococcus

Streptococcus A,B,C,G

S.pneumoniae

Other streptococci

H.influenzae

M.catarr-halis

N.gonorrhoeae

N.meningitidis

Gram-negative anaerobes

Gram-positive anaerobes

B C

Clarithromycin ’

1/2

0.25/

0.5

0.25/

0.5

1/32^d

0.25/

0.5

A. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the table or footnotes

However, pharmacodynamic data for calculation of macrolide, lincosamines and streptogramins non-species related breakpoints are not robust, hence IE.

B. Erythromycin can be used to determine the susceptibility of the listed bacteria to the other macrolides (azithromycin, clarithromycin and roxithromycin

C. Clarithromycin is used for the eradication of H. pylori (MIC <0.25 mg/L for wild type isolates).

D. The correlation between H. influenzae macrolide MICs and clinical outcome is weak. Therefore, breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate.

Clarithromycin is used for the eradication of H. pylori; minimum inhibitory concentration (MIC) < 0.25 pg/ml which has been established as the susceptible breakpoint by the Clinical and Laboratory Standards Institute (CLSI).

The prevalence of acquired resistance rates may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of an agent in at least some types of infections is questionable.

Susceptibility:

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalance of resistance is such that the utility of the agent in atleast some types of infections is questionable.

Commonly susceptible species_

Aerobic, Gram-positive microorganisms_

Streptococcus group F_

Corynebacterium diptheriae

Aerobic, Gram-negative microorganisms_

Bordetella pertusis_

Moraxella catarrhalis_

Pasteurella multocida_

Legionella spp._

Anaerobic microorganisms_

Clostridium spp., other than C. difficile_

Other microorganisms_

Mycoplasma pneumoniae_

Chlamydia trachomatis_

Clamydophila pneumoniae_

Clamydophilapsitacci_

Mycobacterium spp._

Species for which acquired resistance may be a problem#

Aerobic, Gram-positive microorganisms_

Streptococcus group A*, C, G_

Streptococcus group B_

Streptococcus viridans

Enterococcus spp+_

Staphylococcus aureus, methicillin-susceptible and methicillin-resistant+_

Streptococcus pneumoniae *+_

Staphylococcus epidermidis+_

Aerobic, Gram-negative microorganisms_

Haemophilus influenzae$_

Helicobacter pylori_

Anaerobic microorganisms_

Bacteroides spp._

Peptococcus/Peptostreptococcus spp._

Inherently resistant microorganisms_

Aerobic, Gram-negative microorganisms_

Pseudomonas aeruginosa_

Acinetobacter_

Enterobacteriacea_

Anaerobic microorganisms_

Fusobacterium spp._

Other microorganisms_

Mycobacterium tuberculosis_

# > 10% resistance in at least one country of the European Union

* Species against efficacy has been demonstrated in clinical investigations (if susceptible)

+ Indicates species for which a high rate of resistance (i.e. greater than 50%) have been observed in one or more area/country/region(s) of the EU § Breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate

Other information:

Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to clarithromycin can be predicted by testing erythromycin.

Most available clinical experience from controlled randomised clinical trials indicate that clarithromycin 500 mg twice daily in combination with another antibiotic e.g. amoxicillin or metronidazole and e.g. omeprazole (given at approved levels) for 7 days achieve > 80% H. pylori eradication rate in patients with gastro-duodenal ulcers. As expected, significantly lower eradication rates were observed in patients with baseline metronidazole-resistant H. pylori isolates. Hence, local information on the prevalence of resistance and local therapeutic guidelines should be taken into account in the choice of an appropriate combination regimen for H. pylori eradication therapy. Furthermore, in patients with persistent infection, potential development of secondary resistance (in patients with primary susceptible strains) to an antimicrobial agent should be taken into the considerations for a new retreatment regimen.

5.2 Pharmacokinetic properties

Absorption:

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract - primarily in the jejunum - but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of a 250-mg clarithromycin tablet is approximately 50%. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, clarithromycin tablets may be given without regard to food. Due to its chemical structure (6-O-Methylerythromycin) clarithromycin is quite resistant to degradation by stomach acid. Peak plasma levels of 1 - 2 pg/ml clarithromycin were observed in adults after oral administration of 250 mg twice daily. After administration of 500 mg clarithromycin twice daily the peak plasma level was 2.8 pg/ml.

After administration of 250 mg clarithromycin twice daily the microbiologically active 14-hydroxy metabolite attains peak plasma concentrations of 0.6 pg/ml. Steady state is attained within 2 days of dosing.

Distribution:

Clarithromycin penetrates well into different compartments, with an estimated volume of distribution of 200-400 L. Clarithromycin provides concentrations in some tissues that are several times higher than the circulating level of the active substance. Increased levels have been found in both tonsils and lung tissue. Clarithromycin also penetrates the gastric mucus.

Clarithromycin is approximately 70% bound to plasma proteins at therapeutic levels.

Biotransformation and elimination:

Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism is in the liver involving the P450 cytochrome system. Three metabolites are described: N-demethyl clarithromycin, decladinosyl clarithromycin and 14-hydroxy clarithromycin.

The pharmacokinetics of clarithromycin is non-linear due to saturation of hepatic metabolism at high doses. Elimination half-life increased from 2-4 hours following administration of 250 mg clarithromycin twice daily to 5 hours following administration of 500 mg clarithromycin twice daily. The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration of 250 mg clarithromycin twice daily.

Approximately 20 -40% of clarithromycin is excreted as the unchanged active substance in the urine. This proportion is increased when the dose is increased. An additional 10% to 15% is excreted in the urine as 14-hydroxy metabolite. The rest is excreted in the faeces. Renal insufficiency increases clarithromycin levels in plasma, if the dose is not decreased.

Total plasma clearance has been estimated to approximately 700 ml/min (11.7 ml/s), with a renal clearance of approximately 170 ml/min (2.8 ml/s).

Special populations:

Renal impairment: Reduced renal insufficiency function results in increased plasma levels of clarithromycin and the active metabolite levels in plasma.

5.3 Preclinical safety data

In 4-week-studies in animals, toxicity of clarithromycin was found to be related to the dose and to the duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which lesions were seen within 14 days in dogs and monkeys. The levels of systemic exposure at which this toxicity occurred are not known in detail, but toxic doses (300 mg/kg/day) were clearly higher than the therapeutic doses recommended for humans. Other tissues affected included the stomach, thymus and other lymphoid tissues as well as the kidneys. At near therapeutic doses conjunctival injection and lacrimation occurred only in dogs. At a dose of 400mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema.

In vitro and in vivo studies showed that clarithromycin did not have genotoxic potential.

Studies on reproduction toxicity showed that administration of clarithromycin at doses 2x the clinical dose in rabbit (iv) and 10x the clinical dose in monkey (po) resulted in an increased incidence of spontaneous abortions. These doses were related to maternal toxicity. No embryotoxicity or teratogenicity was generally noted in rat studies. However, cardiovascular malformations were observed in two studies in rats treated with doses of 150 mg/kg/d. In mice at doses 70x the clinical dose, cleft palate occurred at varying incidences (3-30%).

Clarithromycin has been found in the milk of lactating animals.

In 3-day old mice and rats, the LD50 values were approximately half those in adult animals. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported in some studies. Slight reductions in erythrocytes, platelets and leukocytes have also been found in juvenile animals.

Clarithromycin has not been tested for carcinogenicity.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Cellulose, microcrystalline Croscarmellose sodium Colloidal Anhydrous silica Magnesium stearate Povidone (K-30)

Film-coat:

Hypromellose Propylene Glycol Titanium Dioxide (E 171) Hydroxypropyl Cellulose Vanillin Sorbic acid

Iron oxide yellow (E 172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC /PVdC/Aluminium blister:

Pack sizes: 500mg:

1, 2, 4, 5, 6, 7, 8 10, 12, 14, 15, 16, 18, 20, 21, 24, 28, 30, 32, 42, 45, 49, 50, 56, 60, 70, 84, 90, 100, 140, 168, 250, 500 or 1000 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed off in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Amneal Pharma Europe Limited 70 Sir John Rogerson’s Quay,

Dublin 2,

Ireland.

8 MARKETING AUTHORISATION NUMBER(S)

PL 42357/0041

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 17/11/2010

10 DATE OF REVISION OF THE TEXT

25/03/2015